Project III: Stress Circuits and Sex Differences in Drug Seeking (Aston-Jones) There is growing evidence for a relationship between stress reactivity and substance use disorders that differ by gender. Brain norepinephrine (NE) and corticotropin releasing factor (CRF) systems are important in stress responses. Recent findings indicate a link between the sex/gender differences in drug abuse and these brain systems: LC-NE neurons in females are more responsive to stressors and to CRFI receptor activation than in males. In addition, oxytocin (OT) neurons are involved in reward processes, perhaps via interactions with NE and CRF, and may play a role in drug craving. In this project we will characterize the roles of these systems in sex/gender-specific drug seeking using behavioral pharmacology and Fos immunohistochemistry in rodent model of cocaine seeking. We hypothesize that sex differences in the CRF-NE system facilitate increased cocaine seeking in females; specifically, we propose that the stress of eariy abstinence increases CRF input to LC, and that the higher response of LC-NE neurons to CRF in females leads to greater cocaine seeking and more difficulty in maintaining abstinence. We will test these ideas by (i) determining the ability of beta adrenoceptor or CRFI receptor antagonists to attenuate cocaine seeking during early abstinence, (ii) identifying NE and CRF neurons that are Fos-activated during eariy cocaine abstinence, and (iii) determining if CRFI receptor antagonism within LC attenuates cocaine seeking during eariy abstinence. Findings here will inform Projects 1 and 4 about circuitry and neurotransmitters involved in drug seeking in their clinical subjects, and Project 2 about upstream circuits that may influence the peptide systems studied there. RELEVANCE (See instructions): This project will define the roles of specific brain systems in sex/gender differences in the initiation of abstinence from cocaine abuse. Results of these studies will lead to more effective treatments for addiction' in both males and females.